New method for synthesizing 2 arylquinazoline and quinazolinone

VIETNAM NATIONAL UNIVERSITY–HO CHI MINH CITY HO CHI MINH UNIVERSITY OF TECHNOLOGY NGUYEN KHANH DUYEN NEW METHOD FOR SYNTHESIZING 2-ARYLQUINAZOLINE AND QUINAZOLINONE Major: Chemical Engineering Number: 8520301 MASTER THESIS HO CHI MINH CITY, SEPTEMBER 2020 ACKNOWLEGDMENT At first, I would like to express my sincere gratitude to all teachers of Faculty of Organic Chemistry of Ho Chi Minh city University of Technology, especially Prof Dr Phan Thanh Son Nam and Dr Nguyen Thanh Tung – my supervisors Besides, I also want to thank to co-workers – Pham Hoang Phuc, Nguyen Xuan Khang – whose expertise, understanding, generous guidance and support made it posible for me to work on my topic It was a pleasure working with them In addition, I want to say thanks to Minh Duy, Hoang Khang and others - my lab member, who always accompany and support me during my studying time at Manar laboratory Finally, I would like to show my respect and gratitude to my family – who always support and help me complete my thesis effectively NGUYEN KHANH DUYEN i ABSTRACT In this master thesis, I would like to present two new protocol that obtained heterocylclic containing nitrogen compounds, especially quinazoline and quinazolinone compounds In the first work, using sulfur as promoter for the synthesizing reaction 2arylquinazoline that has more advantages compared to previous works such as short reaction time, using sulfur has lower toxicity than traditional transition – metal catalysts, low usage amount; at the same time, the applicability of the reaction system has been demonstrated through a variety of 2-arylquinazoline derivatives synthesized based on a wide variety of agents In the second study, a novel C–H bond activation of isoquinoline and 2-aminobenzyl alcohol was explored to form quinazolinone derivatives using copper salt catalyst Mentioned reaction has more advantages compared to previous works such as short reaction time, using transition – metal catalysts This reaction was successfully developed on various derivatives TÓM TẮT LUẬN VĂN Luận văn trình bày hai phương pháp để tổng hợp khung quinazoline quinazolinone Phần thứ luận văn giới thiệu phương pháp tổng hợp quinazoline sử dụng lưu huỳnh làm tác nhân phản ứng, phản ứng thể nhiều ưu điểm không sử dụng kim loại chyển tiếp, độc hại so với phương pháp truyền thống khác, bên cạnh phản ứng cịn tổng hợp số lượng lớn nhóm 2-phenylquinazoline Trong phản ứng thứ hai, phương pháp dùng để tổng hợp khung quinazolinone giới thiệu, phương pháp có nhiều cải tiến sử dụng xúc tác muối đồng với thời gian phản ứng ngắn phương pháp thành công nhiều loại nhóm khác ii DECLARATION I guarantee this is my own research work with the scientific guidance of Prof Dr Phan Thanh Son Nam and Dr Nguyen Thanh Tung The research contents, results in this topic are honest and unpublished in any form before The data in tables for analysis and comment are collected by the author from various sources in the reference section In addition, the thesis also uses some comments and assessments as well as data from other authors and other organizations which are cited and annotated If any fraud is found, I will take full responsibility for the content of my thesis HCM University of Technology is not related to violation of copyright caused by me during the implementation process (if any) Ho Chi Minh city, September 2020 NGUYEN KHANH DUYEN iii TABLE OF CONTENTS ACKNOWLEGDMENT i ABSTRACT ii DECLARATION iii TABLE OF CONTENTS iv LIST OF ABBREVIATIONS vi LIST OF FIGURE vii LIST OF SCHEMES viii LIST OF TABLES xi CHAPTER 1: LITERATURE REVIEW 1.1 Introduction 1.2 The synthesis of quinazolines 1.3 Approaches organic synthesis using sulfur-mediated catalysts 17 1.4 The aim and objectives of our approach 20 1.5 The synthesis of quinazolinones 21 1.5.1.The C2 activation and Csp2 –N coupling reaction in organic synthesis 21 1.5.2.Advanced in the synthesis of quinazolinones 26 1.6 Our approach 30 CHAPTER 2: EXPERIMETAL 31 2.1 Materials and instrumentals 31 2.2 Reaction procedure for synthesis quinazolines derivatives 32 2.2.1.The general procedure for quinazoline derivatives synthesis reaction 32 iv 2.2.2.Isolated product procedure 33 2.2.3.Gram-scale reaction for quinazoline 33 2.3 Reaction procedure of reaction forming quinazolinones 34 2.3.1.The general procedure for synthesis of quinazolinones derivatives 34 2.3.2.Isolated product procedure 34 CHAPTER 3: RESULTS AND DISCUSSION 36 3.1 Studies of reaction conditions of quinazolines 36 3.2 Effect of different substituents of the reaction 47 3.3 Control experiments and proposed mechanism 54 3.4 Studies of reaction conditions of quinazolinones 59 3.4.1.Study of many different conditions on the yield of quinazolinones product 59 3.4.2.The result of synthesis reaction quinazolinone derivatives 65 CONCLUSION 67 REFERENCES 69 APPENDICES 78 v LIST OF ABBREVIATIONS DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCB 1,2-dichlorobenzene DCE 1,2-dichloroethane DMAc N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMEDA N,N’-dimethylehtylenediamine DMF N,N’-dimethylformamide DMSO Dimethylsulfoxide Dppf 1,1’-bis(diphenylphosphino)ferrocene DTBP di-tert-butyl peroxide FT-IR Fourier Transform Infrared GC Gas Chromatography GC-MS Gas Chromatography – Mass Spectrometry NMP N-methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance PXRD Powder X-ray Diffraction Rt Room temperature SEM Scanning Electron Microscopy TBHP tert-butyl hydroperoxide TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy radical TMC Transition Metal Chalcogenide TMD Transition Metal Dichalcogenide TMEDA N,N,N’,N’-tetramethylethylenediamine vi LIST OF FIGURE Figure 1 Quinazoline and its isomers Figure Quinazoline and its derivatives with biological activity Figure The 2-arylquinazoline derivatives have applications in luminescent and bioactive materials Figure The analysis of synthesis of 2-arylquinazoline substituted-derivatives via breaking C2-bond Figure Effect of base on reaction synthesis of quinazolines 38 Figure The yield of main product in various kinds of base 39 Figure 3 The effect of DABCO on the reaction 40 Figure The effect of different kinds of nitrogen source on reaction 42 Figure Effect of urea amount on the yield of product 43 Figure Effect of different molar ratio of starting reactants 44 Figure The effect of amount of elemental sulfur on yield of product 45 Figure Effect of different solvent on the yield of product 46 Figure The effect of different promoters on quinazolines synthesis 47 Figure 10 Effect of temperature on the yield of quinazolinone product 60 Figure 11 Effect of different types of acid on the yield of quinazolinone product 61 Figure 12 The molar ratio effect on the yield of main product 62 Figure 13 The various kinds of catalyst effect on yield of product 63 Figure 14 Effecting the amount of catalyst on reaction 63 Figure 15 Effect of different solvent on synthesis of quinazolinone 64 vii LIST OF SCHEMES Scheme 1 Coupling reaction of 2-cloroquinazoline and arylboric acid by using Pd catalysts Scheme Synthesis of substituted derivatives of 2,4-disubstituted quinazoline via Suzuki coupling reaction of a) Prabhakar and co-workers b) Kakad and coworkers Scheme Synthesis of 2-(1H-indol-1-yl)quinazoline derivatives via BuchwaldHartwig coupling reaction using Ni catalysts Scheme Aggregation of carbazole – quinazoline by Ullmann – Goldberg using CuCl catalysts Scheme Synthesis of quinazoline derivatives via Ullmann-Goldberg coupling reaction from 2-halobenzaldehydes and amidine derivatives Scheme Synthesis of quinazoline derivatives from o-bromobenzyl (pseudo)halides and amidine derivatives via Ullmann-Goldberg coupling reaction Scheme Synthesis of 2-arylquinazoline derivatives via cyclization of Narylamidine and carbonyl equivalent derivatives 10 Scheme Synthetic reaction of 2-arylquinazoline derivatives from 2aminobenzylamines and benzaldehydes using redox catalytic system in the presence of oxygen 11 Scheme Synthesis of quinazoline derivatives from 2-aminobenzylamines and benzyl alcohols 12 Scheme 10 Synthesis of quinazoline derivatives from 2-aminobenzylamine and equivalent benzaldehyde 13 Scheme 11 Synthesis of quinazoline derivatives from 2-aminobenzylamines and equivalent derivatives of benzaldehyde without transition metal catalysts 14 Scheme 12 Synthesis of quinazoline derivatives from 2-aminobenzyl alcohol derivatives and benzonitriles 14 viii Scheme 13 Synthesis of quinazoline derivatives from benzylamine derivatives 15 Scheme 14 General process to synthesize 2-arylquinazoline derivatives 16 Scheme 15 Synthesis of quinazolines towards hydrogen transfer strategy 16 Scheme 16 Synthesis arylbenzothiazole derivatives by Guntreddi and coworkers 17 Scheme 17 Using elemental sulfur in organic synthesis in 2017 18 Scheme 18 Reactions using elemental sulfur in 2018 19 Scheme 19 Reactions using elemental sulfur in 2019 20 Scheme 20 Using elemental sulfur in organic synthesis in 2020 20 Scheme 21 C-H coupling reaction were reported in 2013 22 Scheme 22 C2 activation reaction of quinoline structures in organic synthesis.23 Scheme 23 Coupling reaction via C –H activation in 2016 23 Scheme 24 C2 selective and C –N bond formation reaction in 2017 25 Scheme 25 C2 activation and Csp2–N coupling reaction from 2018 to 2019 26 Scheme 26 The reaction synthesis of quinazolinone in 2011 26 Scheme 27 The synthesis reaction of quinazolinone in 2013 and 2014 27 Scheme 28 Synthesizing of quinazolinone derivatives in 2015 28 Scheme 29 The synthesis reaction of quinazolinone in 2016 and 2017 29 Scheme 30 The reaction of synthesis quinazolinone derivatives in 2018 and 2019 30 Scheme General procedure of synthesis quinazolines 32 Scheme 2 General procedure of synthesis quinazolinones 34 Scheme Reaction model to investigate synthesis of quinazoline 36 Scheme Investigation of the temperature on reaction 37 Scheme 3 Investigation of base on reaction 38 ix DMSO:Ch 67 62 lorobenze ne DMSO: p- 68 62 xylene 69 DMF:H2O 28 70 DMF 1.5) 83 71 DMF (1.8) 82 129 Appendix 48: 1H-NMR spectrum of 9aa 130 Appendix 49: 13C-NMR spectrum of 9aa Charaterization Data for 8H-isoquinolino[1,2-b]quinazolin-8-one (9aa) Yield 82%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 9.01 (d, J= 5Hz, 1H), 8.57 (d, J = Hz, 1H), 8.38 (d, J = Hz, 1H), 7.80 (m, 1H), 7.60 (m, 3H), 7.44(t, J= 10 Hz, 1H) 6.69 (d, J=5Hz, 1H) 13C NMR (126 MHz, CDCl3, ppm) δ 159.4, 147.4, 147.2, 134.9, 132.9, 132.2, 128.5, 127.4,127.3, 126.5, 125.8, 121.9, 117.7, 113.3 131 Appendix 50: 1H-NMR spectrum of 9ab 132 Appendix 51: 13C-NMR spectrum of 9ab Charaterization Data for 5-bromo-8H-isoquinolino[1,2-b]quinazolin-8-one (9ab) Yield 86%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 9.01 (d, J= 5Hz, 1H), 8.57 (d, J = Hz, 1H), 8.38 (d, J = Hz, 1H), 7.80 (m, 1H), 7.60 (m, 3H), 7.44(t, J= 10 Hz, 1H), 6.69 (d, J=5Hz, 1H) 13C NMR (126 MHz, CDCl3, ppm) δ 158.3, 147.2, 145.1, 135.0, 132.7, 131.8, 129.3, 127.7, 127.4, 126.4, 121.9, 126.1, 109.9 133 Appendix 52: 1H-NMR spectrum of 9ac 134 Appendix 53: 13C-NMR spectrum of 9ac Charaterization Data for 4-bromo-8H-isoquinolino[1,2-b]quinazolin-8-one (9ac) Yield 83%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 8.99 (d, J= 5Hz, 1H), 8.63 (d, J = 10 Hz, 1H), 8.41 (d, J = Hz, 1H), 7.90 (d, J = Hz, 1H), 7.83 (m, 2H), 7.50 (ddd, J= Hz, 1H), 7.44(t, J= 10 Hz, 1H), 7.34 (d, J=5Hz, 1H) 13 C NMR (126 MHz, CDCl3, ppm) δ 159.1, 147.3, 145.3, 135.9, 134.0, 132.1, 129.3, 128.9, 127.6, 127.3, 126.6, 126.1, 123.1, 121.4, 117.7, 111.3 135 Appendix 54: 1H-NMR spectrum of 9ad 136 Appendix 55: 13C-NMR spectrum of 9ad Charaterization Data for 4-amino-8H-isoquinolino[1,2-b]quinazolin-8-one (9ad) Yield 52%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 8.44 (d, J= 10Hz, 1H), 8.33 (d, J = 10 Hz, 1H), 8.21 (d, J = Hz, 1H), 7.94 (t, J= Hz, 1H), 7.85 (d, J= 5Hz, 1H), 7.57 (t, J= Hz, 1H), 7.51(d, J= Hz, 1H), 7.42 (t, J=5Hz, 1H), 7.04(d, J=10 Hz, 1H), 5.99(s, 2H) 13C NMR (126 MHz, CDCl3, ppm) δ 159.1, 147.6, 146.8, 135.4, 134.0, 129.7, 128.1, 127.7, 127.1, 126.0, 119.2, 117.6, 116.5, 114.5, 109.1 137 Appendix 56: 1H-NMR spectrum of 9ae 138 Appendix 57: 13C-NMR spectrum of 9ae Charaterization Data for 4-amino-8H-isoquinolino[1,2-b]quinazolin-8-one (9ad) Yield 68%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 10.9 (s,1H), 8.44 (d, J= 10Hz, 1H), 8.59 (d, J = 10 Hz, 1H), 8.35 (d, J = Hz, 1H), 7.97 (t, J= 10 Hz, 1H), 7.90 (d, J= 5Hz, 1H), 7.72 (t, J= 10 Hz, 1H), 7.61(t, J= 10Hz, 1H), 7.39 (d, J=10Hz, 1H), 2.21(s, 3H) 13C NMR (126 MHz, CDCl3, ppm) δ 169.8, 159.1, 147.5, 146.2, 135.6, 134.2, 129.0, 128.1, 127.8, 127.5, 126.4, 123.9, 121.9, 117.8, 109.0, 23.9 139 Appendix 58: 1H-NMR spectrum of 9ca 140 Appendix 59: 13C-NMR spectrum of 9ca Charaterization Data for 12-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (9ca) Yield 88%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 8.96 (d, J= 10Hz, 1H), 8.51 (d, J = 10 Hz, 1H), 8.19 (d, J = Hz, 1H), 7.6 (t, J= 10 Hz, 1H), 7.52 (m, 2H), 7.29 (t, J= 10 Hz, 1H), 6.89(d, J= 10Hz, 1H), 2.70(s, 3H) 13C NMR (126 MHz, CDCl3, ppm) δ 159.7, 146.0, 144.89, 135.9, 132.7, 132.0, 128.4, 128.9, 127.2, 126.4, 125.4, 125.0, 121.2, 117.6, 113.1, 17.5 141 Appendix 60: 1H-NMR spectrum of 9aq 142 Appendix 61: 13C-NMR spectrum of 9aq Charaterization Data for 5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (9aq) Yield 75%, white solid 1H NMR (500 MHz, CDCl3, ppm) δ 8.46 (d, J= 10Hz, 1H), 8.26 (d, J = 10 Hz, 1H), 7.76 (d, J = Hz, 1H), 7.70 (t, J= 10 Hz, 1H), 7.41 (m, 2H), 7.23 (d, J= 10 Hz, 1H), 4.36(t, J= 10Hz, 2H), 3.05(t, J= 10 Hz, 2H) 13C NMR (126 MHz, CDCl3, ppm) δ 161.6, 150.0, 137.2, 134.4, 132.0, 128.8, 127.7, 127.5, 127.4, 127.4, 127.3, 127.0, 126.7, 120.6, 39.7, 27.47 143 ... activation in 20 16 23 Scheme 24 C2 selective and C –N bond formation reaction in 20 17 25 Scheme 25 C2 activation and Csp2–N coupling reaction from 20 18 to 20 19 26 Scheme 26 The reaction... synthesis of quinazolinone in 20 11 26 Scheme 27 The synthesis reaction of quinazolinone in 20 13 and 20 14 27 Scheme 28 Synthesizing of quinazolinone derivatives in 20 15 28 Scheme 29 The synthesis... oxidants, K2CO3 base and CH3NO2 solvent successfully given various derivatives (scheme 1 .22 c) [84] 22 Scheme 1 .22 C2 activation reaction of quinoline structures in organic synthesis In 20 16, Ruch and